Mechanisms of Abeta-Stimulated ROS in Microglia

描述（由申请人提供）： 该提案的目标是阐明介导小胶质细胞对纤维状β淀粉样蛋白（fAa）的促炎反应的机制。小胶质细胞与Abeta斑块的相互作用导致促炎信号级联的诱导和神经毒性分泌产物的释放。先前的研究表明fAbeta刺激的ROS产生来自小胶质细胞NADPH氧化酶的激活。NADPH氧化酶由膜相关黄素蛋白细胞色素b558和胞质p47phox、p67phox、p40phox和Rac 1组成。Rac必须与GTP结合，才能作为氧化酶的一部分发挥作用。胞质组分p47phox和p67phox处于磷酸化和易位到膜以启动ROS产生的状态。关于负责这种激活的Abeta刺激的细胞内信号通路知之甚少。我们推测，fAbeta参与一个新发现的多受体细胞表面复合物的小胶质细胞导致的ROS和随后的神经元损伤的生产。该提案旨在鉴定基于酪氨酸激酶的信号级联，其激活细胞内信号元件，这些元件在暴露于fAbeta后起到刺激NADPH氧化酶组装和激活的作用。

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate mechanisms mediating the microglia pro-inflammatory response to fibrillar beta amyloid (fAa). The interaction of microglia with Abeta plaques leads to the induction of proinflammatory signaling cascades and the release of neurotoxic secretory products. Previous studies have shown fAbeta-stimulated ROS production from the activation of microglial NADPH oxidase. The NADPH oxidase consists of the membrane associated flavoprotein cytochrome b558 and the cytosolic, p47phox, p67phox, p40phox, and Rac1. Rac must be GTP-bound to function as part of the oxidase. The cytosolic components, p47phox and p67phox, under go phosphorylation and translocation to the membrane to initiate ROS generation. Little is known about the Abeta-stimulated intracellular signaling pathways responsible for this activation. We hypothesize that fAbeta engagement of a newly discovered multireceptor cell surface complex on microglia leads to the production of ROS and subsequent neuronal damage. This proposal seeks to identify tyrosine kinase-based signaling cascades that activate intracellular signaling elements that function to stimulate assembly and activation of the NADPH oxidase following exposure to fAbeta.